喜树碱衍生物N-乙酰-Asp-Gly-CPT的药代动力学研究

Study on the Pharmacokinetics of Camptothecin Derivative N-acetyl-Asp-Gly-CPT

建立一种同时检测大鼠血浆中N-乙酰-Asp-Gly-CPT及其主要代谢产物CPT的方法,并对其血浆药代动力学进行初步研究。大鼠尾静脉给药3 mg/kg N-乙酰-Asp-Gly-CPT注射液(2 mg/mL),于给药后0.03、0.08、0.25、0.5、1、2、3、4、6、8、10、12、24和48 h取血,血液样品经乙酸乙酯提取,采用高效液相色谱-荧光法,测定血药浓度。大鼠尾静脉给药3 mg/kg N-乙酰-Asp-Gly-CPT后,立即达到峰值,药峰浓度Cmax为69.75±4.66 ng/mL,约是CPT(2.69±0.54 ng/mL)的27倍;N-乙酰-Asp-Gly-CPT和CPT的半衰期(T1/2)分别为2.93±0.93 h和5.39±0.27 h,平均驻留时间(MRT)分别是5.43±1.05 h和6.95±0.40 h。建立的HPLC方法可成功用于尾静脉给药N-乙酰-Asp-Gly-CPT大鼠血浆药动学研究,N-乙酰-Asp-Gly-CPT和CPT在血浆中具有一定的稳定性,不会被迅速代谢。

The aim of this study is to establish a method for simultaneous determination of N-acetyl-aspartic acidglycine-camptothecin and its main metabolite CPT in rat plasma, and to conduct a preliminary study on its plasma pharmacokinetics. Rats were given 3 mg/kg N-acetyl-ASP-Gly-CPT by tail vein, and blood samples were collected at0.03, 0.08, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 and 48 h after administration. Blood samples were extracted by ethyl acetate, and the concentration of the drug was determined by HPLC. After administered with 3 mg/kg N-acetyl-Asp-GlyCPT, the peak concentration of N-acetyl-Asp-Gly-CPT was 69.75±4.66 ng/mL, nearly 27 times of that of CPT(2.69±0.54 ng/mL). The half-life of N-acetyl-Asp-Gly-CPT and CPT was 2.93 ±0.93 h and 5.39 ±0.27 h, and the mean residence time MRT was 5.43 ±1.05 h and 6.95±0.40 h, respectively. The established HPLC method can be successfully used for the pharmacokinetic study of N-acetyl-Asp-Gly-CPT in rat plasma. N-acetyl-Asp-Gly-CPT was stable in plasma and was not rapidly metabolized.